Humans are afflicted with a wide variety of neurodegenerative diseases, especially of the cerebral cortex and striatum, which result in neuropsychiatric disturbances. Key anatomical and neurochemical characteristics of certain neuropathologic conditions can be replicated in experimental animals by local injections of quinolinic acid (QUIN), an endogenous metabolite of tryptophan (TRP). QUIN has proved to be a potent neurotoxin and convulsant and may therefore be involved in human neuropathology. To investigate such a role, we developed a sensitive, accurate and specific assay for QUIN in brain and cerebrospinal fluid (CSF). We found that brain QUIN is increased by systemic TRP and 3-hydroxyanthranilic acid (3-OHAA) loads. Inhibition of TRP metabolism by pyrazinamide (PYR) facilitates increases in QUIN following TRP administration. These findings are consistent with an etiologic role of QUIN in glutaric aciduria type I, a pediatric disorder associated with impaired metabolism of TRP.